The dramatic decline in the morbidity and mortality associated with atherosclerotic cardiovascular disease (CVD) in the last 50 years is attributable in part to the identification of risk factors, the development of relevant therapies, their evaluaton in clinical trials, and the widespread adoption of those treatments by patients and physicians. Prospective cohort studies have provided some of the most reliable evidence about whether risk factors are likely to be a cause or a consequence of disease. Among individuals with the same levels of traditional risk factors, the risk of CVD varies widely, and part of this variation in evnt rates is likely to be the result of inter-individual variation in the type and intensity of the innte and adaptive- immune inflammatory responses that influence the development and progression of atherosclerosis. Advances in vascular biology have identified the specific roles that various lymphocyte subsets have in the chronic inflammatory disease called atherosclerosis. The goal of this research is to evaluate prospectively whether the densities of specific lymphocyte subsets are novel independent risk factors for the incidence of myocardial infarction (MI) and the composite of MI and new-onset angina (ANG). The proposed case- cohort study is nested within the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Several pilot studies have demonstrated that the cryopreserved samples from CHS and MESA are well suited to the study aims. Using flow cytometry to characterize the innate and adaptive-immune lymphocytes from cryopreserved cells (1998-99 in CHS and 2000-02 in MESA), we will assay 16 different lymphocyte subsets in 1200 MESA and 1200 CHS participants. With adjustment for multiple testing, the primary aim is to evaluate the association of each of the 16 lymphocyte subsets with the two primary outcomes, MI and the composite of first MI and new-onset ANG. The 16 lymphocyte subsets cluster into three groups: 1) high levels of pro-inflammatory cells with direct roles in atherosclerosis will increase the risk of CVD events 2) high levels of chronic adaptive-immune activation will increase the risk of CVD events; and 3) high levels of anti-inflammatory cells with antiatherogenic activity will decrease the risk of CVD events. All the T-cell subsets in Group 1, for instance, have a direct role in atherogenesis, plaque progression or plaque instability: indeed, in the vessel wall, they are not biomarkers, but the active agents of atherosclerosis. The proposed case-cohort study in a primary-prevention population will enable us to evaluate the associations of 16 lymphocyte subsets not only with incident coronary events but also with other outcomes. The study has excellent power. Although treatments targeting the immune system have improved the therapeutic options for serious conditions such as rheumatoid arthritis and cancer, the development and use of immune-related therapies in cardiovascular medicine awaits further discovery. Findings from this case-cohort study may yield novel immune targets and new therapeutic approaches.